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Abstract

Introduction

Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics,
risk factors and treatment coverage for ED are not well known.

Method

This study was carried out prospectively in the multinational EULAR Scleroderma Trial
and Research database by amending the electronic data-entry system with the International
Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres
participating in this EULAR Scleroderma Trial and Research substudy were asked to
recruit patients consecutively.

Results

Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile
Function-5 score. Thirty-eight per cent of all participants had severe ED (International
Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than
subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as
alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation
of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with
severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures
and restrictive lung disease. ED was treated in only 27.8% of men. The most common
treatment was sildenafil, whose efficacy is not established in ED of SSc patients.

Conclusions

Severe ED is a common and early problem in men with SSc. Physicians should address
modifiable risk factors actively. More research into the pathophysiology, longitudinal
development, treatment and psychosocial impact of ED is needed.

Introduction

Systemic sclerosis (SSc) is a connective tissue disorder in which vascular alterations
and endothelial damage are prominent and lead to progressive and widespread dysfunction
of various organs. Vascular symptoms such as Raynaud's phenomenon, digital ulcers
and pulmonary arterial hypertension are also a frequent target of diagnostic and therapeutic
efforts [1]. Men with SSc may develop erectile dysfunction (ED), a vascular complication that
is not frequently addressed in studies. Owing to the predominance of the female gender
in SSc, studies of ED in SSc men are more difficult to perform. The available data
from small studies have suggested that ED is more common in SSc than in the normal
population and in other autoimmune diseases [2-4]. ED has been attributed to a vascular process with diminished arterial blood supply
of the corpus cavernosum [5-8], corporeal fibrosis and accumulation of extracellular matrix [5-7].

This study aims to confirm the high prevalence using an unprecedentedly large multicentre
cohort, and to describe hitherto unaddressed SSc characteristics (autoantibody status,
SSc subtype, disease duration) of men with ED, to study SSc-related complications
and nonrelated comorbidities as factors in the development of ED, and to report on
current treatment regimens.

Materials and methods

Data collection

The study was performed using the multinational database of the EULAR Scleroderma
Trial and Research (EUSTAR) group, which was inaugurated in 2004. Participating centres
are required to have local ethics committee approval; patients must provide informed
written consent prior to entry into the Minimal Essential Data Set [9]. Patients must fulfil the American College of Rheumatology classification criteria
for SSc. For the purpose of this study, the Minimal Essential Data Set online electronic
data-entry system - which prospectively follows patients on yearly visits - was amended
by a separate data-entry page with items specific to the ED study. EUSTAR centres
intending to participate in the ED study were displayed in this separate data-entry
system and were asked to provide all men consecutively with the International Index
of Erectile Function-5 (IIEF-5), a self-administered questionnaire that is validated
in several languages, has high retest reliability, and has demonstrated sensitivity
and specificity for detecting treatment-related changes [10]. The IIEF-5 provides a numerical score that is classified into five categories: severe
ED (scores 5 to 7), moderate ED (scores 8 to 11), mild to moderate ED (scores 12 to
16), mild ED (sores 17 to 21), and no ED (scores 22 to 25).

In addition to the IIEF-5 instrument, men were asked to provide information about
the time of ED onset and the use of phosphodiesterase-5 inhibitors for the specific
purpose of ED treatment (not for pulmonary hypertension), as well as intraurethral
or intracavernous prostaglandin preparations. Physicians were also questioned about
factors known to increase the risk for ED, such as hypercholesterolaemia, diabetes
mellitus, stroke, smoking, peripheral macroangiopathy and coronary heart disease.

Statistical analysis

The dataset was analysed using Stata version 11.0 (StataCorp Inc., College Station,
TX, USA). SSc presentations were analysed cross-sectionally for associations between
ED and other clinical features of ED. Continuous data were presented as the mean (±
standard deviation) or the median with interquartile range (IQR) as appropriate, while
binary parameters were presented as percentages. Odds ratios with 95% confidence intervals
and linear regressions were calculated to estimate effect sizes. Variables with P < 0.1 were then entered into a multivariate logistic regression model.

Results

Participants

Twenty-two EUSTAR centres in 13 countries participated in this study, which started
in October 2009. These EUSTAR centres were prospectively following 2,469 women and
463 men (gender ratio 5.3:1). At the time of census in May 2011, the centres had recruited
a total of 130 men for this study. A comparison between study participants and nonparticipants
demonstrates that the participants were representative of the male population in the
EUSTAR centres with respect to important demographic parameters and disease characteristics
such as age, antinuclear antibodies, and disease duration (Table 1). Participants had a higher proportion of puffy hands and digital ulcers, as well
as a higher modified Rodnan skin score, but less frequently an impairment of the diffusion
capacity of the lung for carbon monoxide below 80% of normal. Differences in systolic
pulmonary arterial pressure estimated by echocardiography were statistically significant
but medically less relevant.

Table 1. Characteristics of men that were included in the ED substudy by the 22 participating
centres compared to those not included.

Prevalence of erectile dysfunction in systemic sclerosis

Of the 130 participants, only 23 men (17.7%) had a normal IIEF-5 score (≥ 22). Two
men had not engaged in any sexual activity in the 6 months prior to filling out the
IIEF-5 questionnaire and could therefore neither be attributed to the ED group or
to the non-ED group. The remaining 105 men (81%) had variable degrees of ED. The largest
group of all participants (38%) had severe ED (Figure 1). The median IIEF-5 score of all SSc patients was 13 (IQR 6 to 19). Among the men
with ED, the median IIEF-5 score was 11 (IQR 5 to 16).

Figure 1.Prevalence and severity of erectile dysfunction among the 130 participants. ED, erectile dysfunction; IIEF-5, International Index of Erectile Function-5.

Comorbidities

A number of conditions are associated with ED in the general population. These conditions
include cardiovascular risk factors, medications (antidepressants, sedatives, neuroleptics,
antiepileptics, diuretics), alcoholism, neurological and endocrine disorders, as well
as prostatic disease [8,11,12]. The majority of the participating men had at least one such comorbidity (Table 2). Men with ED more frequently had more than one simultaneous comorbidity than men
with normal erections.

Traditional cardiovascular risk factors such as arterial hypertension, diabetes mellitus,
coronary heart disease, hypercholesterolaemia and smoking were not more prevalent
in men with ED. Significantly more men with ED (13.8%) than those without ED (0%)
consumed alcohol in excess of 2 units per day and twice as many had depression (not
significant). Men with severe ED (IIEF-5 scores 5 to 7) had a low prevalence of alcoholism
(5.7%), but the highest prevalence of depression as judged by the treating physician
(10.8%). Central nervous system dysfunction was reported only in men with ED, in which
it consisted of stroke, multiple sclerosis and dementia. More men with ED than those
without ED had prostatic disease, whereas endocrine or medication-related factors
did not differ between both groups.

Demographics, disease characteristics and predictors of ED

Patients with ED were significantly older than subjects without ED (Table 3). The median SSc duration was similar in both groups (approximately 7 years if measured
from the onset of Raynaud's phenomenon, and 6 years if determined from the first non-Raynaud's
symptom). The median duration of ED was 1.8 years (IQR 0.3 to 4.9). Patients with
more severe ED had experienced erectile problems for a longer time (median of 4 years
in patients with IIEF-5 score ≤ 7) than those with less severe ED. In the majority
of patients, the erectile problem started after the onset of SSc (in 90.1% of SSc
patients after the onset of Raynaud's phenomenon, and in 82.1% of men after the manifestation
of the first non-Raynaud's symptom of SSc). The median time interval from the onset
of the first non-Raynaud's symptom of SSc to the onset of ED was 4.1 years (IQR 1.5
to 8.3 years). An analysis by ED duration revealed a negative correlation between
IIEF-5 score and time of ED (P = 0.03). The IIEF-5 score was not correlated with SSc duration, as measured either from
the onset of Raynaud's phenomenon or from the onset of first non-Raynaud's symptom,
however, and about one-fifth of all men have maintained normal erections many years
after SSc onset (Figure 2).

Figure 2.Severity of erectile dysfunction as a function of disease duration. Figures in bars represent the number of men within each subgroup; y axis, cumulative percentages. ED, erectile dysfunction; SSc, systemic sclerosis.

A total 52.4% of men without ED had one of the antinuclear antibodies typically tested
for SSc; for example, antibodies directed against topoisomerase I (Scl70), centromere,
U1 RNP and RNA polymerase III. Among men with ED these typical antinuclear antibodies
were more prevalent (69.2%) than in men without ED (52.4%), but the difference was
not statistically significant. The prevalence of autoantibodies against topoisomerase
I (Scl70) was similar in the ED group and the non-ED group, but antibodies directed
against centromere, U1RNP and RNA polymerase III were more frequent with ED (Table
3).

The presence of ED was also associated with more severe organ involvement in SSc.
Men with any form of ED had a higher modified Rodnan skin score, and more frequently
had muscle atrophy, a history of renal crisis, elevated pulmonary arterial pressure
and restrictive lung disease (Table 3). Men with ED also had higher EULAR SSc activity scores than men with normal erectile
function [13]. On multivariate analysis, however, only age remained a predictor of ED (P = 0.02, R2 = 0.42).

Treatment of erectile dysfunction

Treatment information was obtained in 101 of the 105 men with ED (Table 5). A total 72.2% of men with abnormal erections did not receive any treatment for
ED. In the remaining 27.8% of men, ED was treated with a phosphodiesterase-5 inhibitor
as the recommended first-line modality in the non-SSc population. Sildenafil was the
agent most commonly used; seven of the 15 men using sildenafil also had concomitant
pulmonary arterial hypertension. Tadalafil was used in a total of 11 men. The proportion
of patients with tadalafil and concomitant pulmonary arterial hypertension was not
captured because the study was launched prior to the approval of tadalafil for pulmonary
arterial hypertension. Two men with moderate ED were treated with intracavernous alprostadil
injections. Three of 101 men with ED (IIEF-5 scores of 10, 16 and 20) received combination
therapy. One man was treated with sildenafil plus vardenafil, one man received sildenafil
plus tadalafil and one man received sildenafil plus intracavernous alprostadil.

Other second-line treatments for ED, such as intraurethral alprostadil applications
or vacuum devices, were not used. Two patients had received a penile prosthesis for
severe ED; one patient had a normal IIEF-5 score after this procedure. The ED in the
second patient who also suffered from multiple sclerosis had not improved from the
otherwise uneventful prosthesis implantation.

Discussion

Connective tissue diseases more frequently affect women and most studies have not
addressed medical problems specific to men. This study represents the largest investigation
so far of ED in men with SSc. The prevalence of ED in our survey is similar to, or
even exceeds, the estimates from smaller studies [3,4] and is considerably higher than in the general population. A study in Massachusetts,
for example, calculated the prevalence of complete impotence as 5 to 15% in men between
40 and 70 years of age in the general population [14]. The prevalence of ED in our study also exceeds estimates in other chronic disease
populations, such as in diabetes mellitus (37 to 75%) [15,16], stroke (48%) [17], and arterial hypertension (23 to 46%) [18-20]. For rheumatoid arthritis the reported prevalence was 48% [4].

Patients with SSc not only have an elevated prevalence of ED, they also have more
severe ED compared with the general population. The average IIEF-5 score in our study
was 13.3, which is similar to the only other study in which ED severity was investigated
in 17 men with SSc [6]. In comparison, the average IIEF-5 score in a non-SSc population with a similar age
was 21.3 [11]. About one-third of men with SSc had severe ED in our investigation, whereas in the
general population only 8.5% of the men with ED reported moderate or severe ED [11]. In men with non-SSc causes of ED - for example, diabetes [15,16], arterial hypertension [18-20], and stroke [17] - the severity of ED was also milder than in SSc.

Although ED manifests after SSc onset in the vast majority of men [4], it appears as a relatively early symptom of SSc with a mean delay from SSc diagnosis
of 2.7 years [4]. ED will probably not become a diagnostic predictor of SSc, given the fact that ED
mostly follows SSc onset. This contrasts with the role of ED in the general population,
in which ED is an important harbinger of subsequent cardiovascular disease [8,21].

Our study confirms age as an important but nonmodifiable risk factor for ED development
in SSc [6]. More importantly, our findings show an association with SSc severity in terms of
restrictive lung disease and renal and pulmonary vasculopathy. Our study also examined
for the first time the relationship between ED and autoantibody status, but failed
to identify a protective antibody or an antinuclear antibody conferring an elevated
risk of ED development. Among the modifiable risk factors of ED, the elevated alcohol
consumption of men with ED deserves attention. The present data, however, do not permit
one to differentiate whether alcohol consumption is a cause of ED, is a coping strategy
for ED, or is unrelated to ED. Although the ED was more frequent in SSc men than in
the normal population and age was an important risk factor for ED, the interpretation
of the SSc effect in our study would be facilitated by the recruitment of a non-SSc
control group matched for known ED risk factors.

Treatment guidelines for ED in the general population suggest that modifiable risk
factors such as lifestyle, psychological or drug-related factors be minimised prior
to or in conjunction with specific ED therapy [12,22]. In our study, about one-fifth of SSc patients had at least one such modifiable comorbidity.
A higher proportion of men with SSc-related ED than those without ED had more than
two comorbidities, indicating that these factors may contribute to the development
of ED not only in the general population but also in patients with SSc and that these
factors should be aggressively addressed. In the non-SSc population, pharmacotherapy
with phosphodiesterase-5 inhibitors is recommended as first-line specific treatment
[22]. In SSc, the efficacy data of phosphodiesterase-5 inhibitors for ED with on-demand
sildenafil were disappointing [23], whereas the longer-acting tadalafil is slightly better evaluated [24,25]. Second-line and third-line treatment options such as vacuum devices or intracavernous
or intraurethral applications of alprostadil were used by only a minority of men with
SSc, and a similar minority was equipped with a penile prosthesis although successful
implantations were previously reported [7].

Our study has both strengths and limitations. It represents the largest analysis of
impotence in men with SSc. The multicentric nature of our investigations may, on the
one hand, be more representative of all men affected by the disease than a monocentric
study, but on the other hand may lead to difficulties in standardising data collection.
Although centres were asked to recruit men consecutively, there is always a risk of
recruitment bias, as indicated by the slight differences observed between participants
and non-participants. Depression was only judged by the treating physician and not
captured with a validated questionnaire. Lastly, it would have been interesting to
correlate the prevalence of ED with changes on nailfold capillaroscopy but these data
were not available in the majority of patients.

Conclusion

Our study indicates that ED is a common, severe and early problem in men with SSc.
ED is associated with a higher age of patients and the presence of restrictive lung
disease, as well as with renal and pulmonary vasculopathy. The reasons for the overall
low treatment coverage were not the assessed in this study but clearly a heightened
awareness among physicians and more research into pathophysiology, longitudinal development,
treatment and psychosocial impact are urgently needed.

Abbreviations

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

UAW participated in the design of the study and statistical analysis and prepared
the manuscript. CF performed the statistical analysis and helped to draft the manuscript.
AT and TH participated in the design of the study and helped to draft the manuscript.
All other coauthors participated in the data acquisition and helped to draft the manuscript.
All authors read and approved the final manuscript.

Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM: Development and evaluation of an abridged, 5-item version of the International Index
of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction.